Adaptation
Evolution is driven by a process called adaptation whereby an organism becomes better able to live in its habitat. Adaptedness is the state of being adapted, the degree to which an organism is able to live and reproduce in a given set of habitats. It is acknowledged that best adapted organisms will have the best chance of survival. Adaptedness is best reached through the body's ability to maintain a state of equilibrium, known as homeostasis, which involves the preservation of physiological functions such as body's temperature, respiratory rate, and blood chemistry, within tightly controlled limits.
Homeostasis
Homeostasis is defined as a balanced physiological state essential for adaptation. Homeostasis is a state in which everything within the cell is in equilibrium and functioning properly. Homeostasis conservation in human body depends on the delicate balance between cell's capacity to maintain metabolism and demand. In order to prevent diseases and other dysfunctions, tissues in our body accomplishes many metabolic reactions to maintain a constancy of environment for the vitality and well-being. At the cell level, to maintain equilibrium or homeostasis, the cell membranes must be in continuous interaction with both the internal (intracellular) environment and the external (extracellular) environment. When the homeostasis of any component is disturbed, the interaction permits automatic readjustment by giving rise to stimuli that result in restoration of metabolic process. The state of homeostasis requires a good transport of important nutrient for the cell to continue to function properly.
Mechanisms of Homeostasis
In General:
Homeostasis processes are involved in the regulation of gut/mucosal epithelial functions and integrity, glucose level/insulin resistance, energy levels, endocrine/stress hormones levels, oxidative stress (respiration), immune/inflammatory state, neurological functions and mitochondria functions. Molecular mechanisms regulating homeostasis involve, among others, TLR activation, calcium influx, ATP production, inflammatory cytokines production, neurotransmitter release, hormonal production, and reactive oxygen species (ROS) production.
Mitochondria-Driven Homeostasis:
Intake of oxygen and nutrients regulate the physiological responses of adaptation. These responses are carried out mainly by mitochondria of eukaryotic cells, also know as the cell's power producers. Through glycolysis, a process that converts glucose into pyruvate, the energy fuel adenosine triphosphate (ATP) is released. Pyruvate is then used by the mitochondria to generate more ATP, representing 90% of all ATP generated, and reactive oxygen species (ROS) through the reduction of the oxygen from the electron transport chain. ROS include the superoxide, oxygen singlet, hydrogen peroxide and hydroxyl. Intracellular ROS, the majority of which is derived from mitochondria (Finkel and Holbrook, 2000), can act as signaling molecules and play important roles in homeostasis (D'Autréaux and Toledano, 2007). However, excessive production of ROS can lead to a situation known as oxidative stress, resulting in a significant damage to cell structures, a process known to be involved in ageing (Finkel and Holbrook, 2000). Oxidative stress plays a role in the pathogenesis of diseases such as diabetes, atherosclerosis, chronic inflammations or cancer (Crimi et al., 2006). In addition to act as a power house, mitochondria also function as signaling platforms to regulate innate protective mechanisms (West et al, 2011). It is not known whether mitochondria activities, through ATP and ROS generation, also drive adaptation.
Toll-Like-Receptors and Homeostasis:
Toll-like receptors (TLRs) are evolutionary-conserved type I transmembrane proteins that act as key regulators of innate defense mechanisms essential to the protection and survival of the organism. Mucosal surfaces, exposed to food, represent critical physical and functional interfaces between the body's internal and external world. TLRs are abundantly expressed at mucosal surfaces, especially in the buccal cavity (Wang et al, 2009) and in villus and crypt intestinal epithelial cells at their apical poles (Didierlaurent at al, 2002; Ortega-Cava 2003). In the general intestinal mucosa, TLRs play a homeostatic role, maintaining the epithelial barrier and preventing responses to TLR agonists on luminal microorganisms (Backhed et al, 2005; Rakoff-Nahoum et al 2004; Abreu 2010). Indeed, deregulation of TLR signaling in the gut can result in chronic inflammatory and excessive and even destructive repair responses that may be associated with diseases like colon cancer and inflammatory bowel diseases (Abreu 2010, Cario 2010). Particularly, the role of mucosal TLR2 in homeostasis is important because it plays a role in gate keeping functions of intestinal epithelial cells (Chabot et al, 2006) and controls mucosal inflammation by regulating epithelial barrier function (Cario et al, 2007, 2008). Although there is evidence that TLR1/2/4 signaling induces mitochondrial ROS generation through TRAF6 and ECSIT interaction to augment macrophage bactericidal activity (West et al, 2011), it is not known whether TLRs also regulate mitochondria-driven homeostasis. A recent study of TLR evolution shows a clear signature of positive selection in their rates of substitution across primates, suggesting TLRs may also play a significant role in adaptation (Wlasiuk and Nachman, 2010)
Neurotransmission and Homeostasis:
Maintaining balanced levels of neurotransmitters contribute to homeostasis. Dopamine (DA) is the key neurotransmitter that regulates the reward, motivation and reinforcement center of the central nervous system (CNS), as well as the hypothalamic-pituitary-adrenal (HPA) axis, known to control stress responses. DA is involved in many motivational behaviors including rewarding, motivation, food intake, food reward, addiction and motor control. Striatum and nucleus accumbens (NAcc) are brain structures where DA is produced, and they are referred sites of control of food reward. It is well documented that DA production in striatum and NAcc is excessive following binge intake of sugar and fat. There is also modification in Ach and opioids systems such as those observed in drug abuse. Binge eating, associated to obesity, afflicting a large proportion of the American adult population, is also associated with depression, anxiety and substance abuse. Serotonin, the neurotransmitter that plays a role in depression and anxiety through the regulation of mood, can also affect dopamine release in the MLDS brain regions.
Active Ingredients
Adaptogens: The concept of “adaptogens” is thousands of years old, and was long considered an important feature of ancient medical systems in parts of Asia and in northern Europe. Although pharmacological evidence is still missing, herbalists claim that adaptogens derived from plants exert a normalizing effect on the body without any risk of creating an unbalanced state, by inducing healthy functions while decreasing unhealthy responses triggered by stress. For that reason, adaptogens are believed to increase resistance to stress, trauma, anxiety and fatigue. It is believed that many antioxidants are indeed adaptogenic. Studies demonstrated that some adaptogenic plants can modulate TLR activity. For example, it was recently shown that the polyphenol epigallocatechin-3-gallate isolated from green tea, have been shown to down regulate TLR4 signal transduction (Byun et al 2010). Also, it was shown that dioscorin, a glycoprotein from Dioscorea alata, is a novel TLR4 activator and induces macrophage activation via typical TLR4-signaling pathways (Fu et al 2006). Another study demonstrated that 9,10-Dihydro-2,5-dimethoxyphenanthrene-1,7-diol, a phenanthrene isolated from Eulophia ochreata of the Orchidaceae family, blocked TLR4-dependent NF-kappaB-regulated inflammatory cytokine production (Datla et al, 2010). It is not known whether plant adaptogens can affect mitochondrial activity through TLR modulation to promote homeostasis.
Antioxidants: Antioxidants are described as molecules capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent that can produce free radicals, which are toxic byproducts of cell metabolism that can start chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions. Antioxidants are often reducing agents such as thiols, ascorbic acid or polyphenols. Although oxidation reactions are crucial for life, they can also be damaging; hence, plants and animals maintain complex systems of multiple types of antioxidants, such as glutathione, vitamin C, and vitamin E as well as enzymes such as catalase, superoxide dismutase and various peroxidases. Low levels of antioxidants, or inhibition of the antioxidant enzymes, cause oxidative stress and may damage or kill cells. The human body naturally produces antioxidant molecules but this process is not totally effective and that effectiveness declines with age. The fundamental nutritional benefit of fruit and vegetables in the prevention of diseases—especially in the light of the current “anti-aging wave” has directed the attention of scientists and consumers to a variety of berry fruits and their constituents. Many berries have a long tradition in European and North American folk medicine. Based on these experiences and due to the growing interest the number of food supplements on the market containing fruit powders, juice concentrates or extracts of these fruits has increased considerably. Advertising for these products mainly focuses on the phenolic compounds, especially the anthocyanins and proanthocyanidins and their preventive effects. Most of the preparations are combinations, e.g. of extracts of different fruits with vitamins and trace elements, etc. which are labeled in a way which does not allow a comparison of the products (Krenn et al, 2007). Antioxidant-rich food include berries (blueberries, blackberries, raspberries, strawberries and cranberries), beans (small red, kidney, pinto and black beans), fruits (apples, avocados, cherries, pears, pineapple, oranges, plums, kiwi), vegetables (Artichoke, spinach, red cabbage, potatoes, broccoli), beverages (green tea, coffee, red wine, fruit juices), nuts (walnuts, pistachios, pecans, hazelnuts and almonds), many herbs and spices, grains, and dark chocolate. Diets deficient in antioxidants can accelerate cell death, mitochondrial decay contributing to the development of chronic diseases, and other dysfunction. Antioxidant deficiency increases oxidative stress, and consequently leads to mitochondrial dysfunction and age-associated diseases, including metabolic syndrome.
Polyphenols: Polyphenols occur ubiquitously in plant foods and structurally have variations in the C ring that characterizes the different types namely, flavonols, flavones, isoflavones, flavonones, flavanol and anthocyanins. Polyphenols are present in large amount of fruits and vegetables as secondary plants metabolites and have a significant impact in preventing many diseases in human (Heim, Tagliaferro, & Bobilya, 2002). Polyphenols are potential adaptogens. It is a widely distributed compound in plants and not only have proprieties associated with food quality such as color and aroma, but also may have potential health benefits, including reduction of cancer risk (Macheix, Fleuriet, & Billot, 1990). According to Thériault at al. (2005), maple syrup (Acer saccharum) contains antioxidant and antiradical activities due to the presence of phenolic compounds. Cranberry polyphenolics, like other dietary polyphenolics, may induce activation mitochondrial apoptosis pathway. This anticancer property lead to tumor cells to apoptosis. The possible effects of cranberry on expression of genes controlling steps in the mitochondrial apoptosis pathway are currently under investigation. The main groups of polyphenols with their individual compounds and food sources are summarized in J. Agric. Food Chem. Vol. 56, No. 13, 2008, in FIG. 1 at page 4858, which is incorporated herein by reference.
Anthocyanins: Anthocyanins are polyphenolic compounds that belongs to the flavonoid family. They are colored (blue-red) pigments abundant in many fruits, vegetables and flowers. They are known to have antioxidant activity (Zafra-Stone et al, 2007). It is easy to presume that anthocyanins are also potential adaptogens. They readily donate hydrogen to form relatively stable unpaired-electron structures, and chelate transition metals such as iron. In the context of the nervous system, anthocyanins have been shown to improve motor and cognitive functions in experimental animals, and to prevent ROS-mediated apoptotic death in neurons (Levites et al., 2002). When mitochondrial proteins integrity is threatened, this may contribute to neurodegenerative disorders along with other apoptogenic mitochondrial disorders. There is evidence that spoiled cytochrome c, a protein in the electron transport chain, can lead to these disorders, and increase oxidative stress, respiratory chain dysfunction, and apoptotic cell death. Moreover, dopamine oxidation in neurons can result in the production of ROS and increase oxidative stress, reduce cytochrome c properties, and, by interfering with normal cytochrome redox cycling, may contribute to dopaminergic neurodegeneration (Mazzio et al. 2004). Yao and Vieira (2007) show that anthocyanins from Vaccinium species are potent inhibitors of dopamine oxidative forms.
Antioxidants and Prevention of Diseases
Antioxidants are said to be extremely good for us in many ways, helping to prevent and keep under control some serious illnesses. Recent research has shown that antioxidants can help with human health and lifestyles in many ways. Enhancement of antioxidant defenses through dietary supplementation is a reasonable and practical approach to help the body fight off chronic diseases such as cancer, cardiovascular diseases, neurodegenerative diseases, chronic inflammatory diseases, and diabetes (Finkel and Holbrook, 2000). Antioxidants help prevent the physiopathology of these diseases which involves the excessive and chronic presence of inflammatory mediators, oxidative stress and cell death. Antioxidants also help slowing down the ageing process and the development of age-related diseases (Finkel and Holbrook, 2000).
The Invention
It has now been found that the combination of antioxidant extracts can mutually potentiate their antioxidant potential. Combinations of antioxidant sweeteners such as maple syrup and a herbal extract (plants and/or herbs) and/or a plant-product extract (fruits and/or vegetables) having antioxidant properties have never been studied. The present invention demonstrates the synergistic effect of these combinations on antioxidant capacity of functional foods or beverages formulations.
It has further been found that combinations of antioxidant-rich extracts possess synergistic effects to modulate mechanisms regulating homeostasis, thereby helping to sustain homeostasis.
It is found that antioxidant-rich formulations developed by Applicant regulate TLR2-dependent oxidative and energetic mitochondrial responses in oral mucosal cells to promote homeostasis, providing important scientific evidence for their role as regulators of adaptation.